Forschungszentrum DZNE12h ago
New paper out: Linking combined oral contraceptive use to systemic immune marker profiles: the role of cortisol.: Klinger-König, Johanna; van der Auwera, Sandra; Töpfer, Philipp; et al.
Frontiers in endocrinology Vol. 17, p. 1796526 http://dlvr.it/TSvt3c | Please share #dzne #papers
Linking combined oral contraceptive use to systemic immune marker profiles: the role of cortisol. - DZNEPUB

Combined oral contraceptive (COC) use has been associated with stress-like, metabolic, and inflammatory alterations. Previous studies demonstrated that metabolic changes were related to cortisol. However, broad immune marker patterns in COC users remain insufficiently characterized, despite evidence of inflammatory involvement. This study investigates COC-related alterations in broad immune marker profiles and whether these are related to cortisol.Data from 392 premenopausal women (128 COC users) of the general population-based SHIP-TREND-0 cohort were analyzed using linear models to estimate differences between COC users and non-users. Immune markers included basic inflammation parameters and a broad panel of cytokines, growth factors, and chemokines. Indirect effects through cortisol were tested in structural equation models.Compared to non-users, COC users had higher cortisol (β=1.24, p<0.001). Higher CRP (β=0.97, p<0.001), and vascular growth factors (i.e., PDGF-AB/BB and VEGF-A; both β=0.27, p<0.05) in COC users were related to cortisol (indirect effects: 0.21 to 0.30; all p<0.05). COC users had fewer monocytes (β=-0.52, p<0.001) and altered chemokine levels (i.e., lower eotaxin and higher MIG levels; β=-0.58 and 0.36, all p<0.001), for which no indirect effects were detected.COC use was associated with broad immune profiling, representing one of the first broad immune marker assessments in COC users. Indirect effects through cortisol suggested both cortisol-dependent and cortisol-independent pathways. These findings provide novel evidence for systemic immunological correlates of COC use and highlight routes of association with endocrine regulation. Klinger-König, Johanna; van der Auwera, Sandra; Töpfer, Philipp; Ameling, Sabine; Friedrich, Nele; Völker, Uwe; Völzke, Henry; Hertel, Johannes; Grabe, Hans J

Forschungszentrum DZNE16h ago
New paper out: Feasibility and Tolerability of Ketogenic Interventions in Amyotrophic Lateral Sclerosis-A Dose-Finding Case Series.: Herrmann, Christine; Satari, Samantha; Weber, Andrea; et al.
Nutrients Vol. 18, no. 10, p. 1628 - http://dlvr.it/TSvkJZ | Please share #dzne #papers
Feasibility and Tolerability of Ketogenic Interventions in Amyotrophic Lateral Sclerosis-A Dose-Finding Case Series. - DZNEPUB

Background/Objectives: Weight loss and hypermetabolism are negative prognostic factors in amyotrophic lateral sclerosis (ALS). Ketone bodies (β-hydroxybutyrate, βHB) as high-energy substrates may compensate for this energy deficit, since a ketogenic diet (KD) has been shown to increase survival and stabilize body weight in the SOD1 mouse model. In this case series, we tested exogenous ketone salts (KS), ketone esters (KE), and a KD, in patients with ALS and in healthy subjects to identify novel therapeutic interventions for subsequent clinical studies. Methods: KS (KetoForce® (KetoSports, Frisco, TX, USA)) were tested in healthy subjects (11.7 g and 15.6 g βHB) and patients (15.6 g βHB 3×/day over 3 days). KE (KE4® (KetoneAid, Falls Church, VA, USA)) containing 10.0 g βHB were applied in healthy subjects (once) and in patients (3×/day over 2 days). For the KD, KetoCal® 2.5:1 LQ MCT MF Vanilla (Nutricia, Frankfurt, Germany) was applied via percutaneous endoscopic gastrostomy over four weeks. Regular capillary βHB measurements were conducted, and adverse events were recorded. Results: Between January 2021 and March 2025, we treated nine patients with ALS and two healthy subjects at the Department of Neurology of Ulm University, Germany. KE and KS increased βHB temporarily. However, the elevation was more pronounced following KE (maximum 2.2-2.7 mmol/L vs. 0.8-1.2 mmol/L). The KD increased βHB levels continuously with nighttime fluctuations. No adverse events occurred under KE. KS caused diarrhea in 3/5 patients and 1/2 healthy subjects. The KD was well tolerated, with mild gastrointestinal symptoms occurring in all patients. Conclusions: All ketogenic approaches increased βHB blood levels. While the KD and KE provided good tolerability, KS caused significant gastrointestinal side effects. KD seems to be an interesting candidate for future clinical studies, as it prompted a long-term increase in βHB while providing satisfying tolerability. Since maintaining a KD long-term is difficult for oral-feeding patients, KE may constitute a feasible alternative. Herrmann, Christine; Satari, Samantha; Weber, Andrea; Ruschitzka, Tanja; Jagodzinski, Luisa; Elmas, Zeynep; Becker, Felicitas; Richter, Lars; Wiesenfarth, Maximilian; Michels, Sebastian; Weishaupt, Jochen H; Schuster, Joachim; Dorst, Johannes

Forschungszentrum DZNE21h ago
New paper out: Tracking of Neuroinflammation Dynamics During Combined Anti-β-Amyloid Therapy (AAT) and Immunomodulation in a Preclinical Alzheimer's Disease Model.: Wind, Karin; Kunze, Lea H; Willem, Michael; et al.
International journal of molecular sciences Vol. 27, no. 10, p. 4632 - http://dlvr.it/TSvZQK | Please share #dzne #papers
Tracking of Neuroinflammation Dynamics During Combined Anti-β-Amyloid Therapy (AAT) and Immunomodulation in a Preclinical Alzheimer's Disease Model. - DZNEPUB

Neuroinflammation is increasingly recognized as a key modulator of therapeutic response and adverse events in Alzheimer's disease (AD), especially during anti-amyloid-β (Aβ) monoclonal antibody (Aβ-mAb) treatment. We applied longitudinal translocator protein (TSPO) positron emission tomography (PET) to evaluate TSPO-associated neuroinflammatory responses to chronic Aβ-mAb therapy and their modulation by the peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone. AppNL-G-F knock-in mice underwent TSPO-PET and Aβ-PET imaging at 5, 7.5, and 10 months of age across four treatment arms: placebo, Aβ-mAb, pioglitazone, and combination therapy. TSPO-PET detected early and progressive neuroinflammatory responses to Aβ-mAb that appeared lower with pioglitazone co-treatment. Both mono- and combination therapy were associated with altered temporal and spatial dynamics of the TSPO-PET signal. In addition, we applied a previously validated microglia desynchronization index based on TSPO-PET connectivity, which captured individual variation in regional TSPO-PET organization and correlated with cognitive performance. Together, TSPO-PET and its regional synchronicity can quantify longitudinal, region-specific treatment effects, which may help differentiate harmful from adaptive neuroinflammatory responses. These findings highlight the potential of TSPO-PET as a stratification biomarker to optimize therapeutic interventions. TSPO-PET therefore enables in vivo tracking of treatment-associated neuroinflammatory responses during anti-Aβ immunotherapy and provides a non-invasive framework for evaluating combination strategies targeting amyloid pathology and immune regulation in AD. Wind, Karin; Kunze, Lea H; Willem, Michael; Palumbo, Giovanna; Giudici, Camilla; Nuscher, Brigitte; Boening, Guido; Gildehaus, Franz J; Lindner, Simon; Werner, Rudolf A; Franzmeier, Nicolai; Gnörich, Johannes S; Brendel, Matthias; Zatcepin, Artem

Forschungszentrum DZNE1d ago
New paper out: Stem-Cell-Derived Biologic Ventricular Assist Tissue in Heart Failure.: Zimmermann, Wolfram-Hubertus; Ensminger, Stephan; Kutschka, Ingo; et al.
The New England journal of medicine Vol. 394, no. 20, p. 1991 - 2001 http://dlvr.it/TSv8Sj | Please share #dzne #papers
Stem-Cell-Derived Biologic Ventricular Assist Tissue in Heart Failure. - DZNEPUB

Biologic ventricular assist tissue (BioVAT) is formulated from engineered heart muscle composed of cardiomyocytes and stromal cells derived from allogeneic induced pluripotent stem cells for cardiac remuscularization in patients with heart failure and a reduced left ventricular ejection fraction.We conducted an open-label, phase 1-2 study of tissue-engineered heart repair by means of BioVAT transplantation. Patients with heart failure and a left ventricular ejection fraction of 35% or less and at least one hypokinetic or dyskinetic left ventricular segment were treated with BioVAT allografts, which consisted of 5, 10, or 20 engineered-heart-muscle units. All the patients received immunosuppression. Safety was assessed as adverse events related to the procedure. The primary efficacy end points were the change from baseline in the target heart-wall thickness, the left ventricular ejection fraction, and the Kansas City Cardiomyopathy Questionnaire-Overall Summary Score (KCCQ-OSS).A total of 20 patients were treated in the study. Three patients died during the study (1 each from vasoplegia, coronavirus disease 2019, and aortic dissection). One patient underwent heart transplantation. Immunosuppression was discontinued in 4 patients because of implantation of a left ventricular assist device (in 2 patients), renal failure (in 1 patient), and urothelial carcinoma (in 1 patient). Of the 16 patients who were treated with the safe maximal dose (20 engineered-heart-muscle units), 12 patients completed the prespecified 3-month interim follow-up. The least-squares mean increase in the target-wall thickness was 4.5 mm (90% confidence interval [CI], 3.7 to 5.4; P<0.001), the increase in the left ventricular ejection fraction was 3.9 percentage points (90% CI, 0.9 to 6.8; P = 0.04), and the increase in the KCCQ-OSS was 6.7 points (90% CI, 1.0 to 12.5; P = 0.06). All the patients had at least one adverse event.In this interim analysis, cardiac remuscularization with BioVAT was associated with an increase in the target heart-wall thickness, left ventricular ejection fraction, and KCCQ-OSS at 3 months; all the patients had at least one adverse event. Longer-term follow-up and further clinical investigation are warranted. (Funded by the German Center for Cardiovascular Research and Repairon; BioVAT-HF ClinicalTrials.gov number, NCT04396899.). Zimmermann, Wolfram-Hubertus; Ensminger, Stephan; Kutschka, Ingo; Paitazoglou, Christina; Seidler, Tim; Brandenburg, Sören; Anker, Stefan D; Bader, Niklas; Bergau, Leonard; Bremmer, Felix; Diogo, Pedro G; Eitel, Ingo; Fujita, Buntaro; Gerecke, Birgit; Hasenfuß, Gerd; Hellenkamp, Kristian; Hermann-Lingen, Christoph; Jebran, Ahmad-Fawad; Jurczyk, Dominik; Knaus, Rainer; Legler, Tobias; Lotz, Joachim; Placzek, Marius; Pühler, Thomas; Riggert, Joachim; Sadlonova, Monika; Saraei, Roza; Ströbel, Philipp; Tiburcy, Malte; Ullrich, Christian; Voigt, Jens-Uwe; Walker, Florian; Wollnik, Bernd; Yigit, Gökhan; Friede, Tim; Investigators, BioVAT-HF; Brandenburg, Sören; Seidler, Tim; Jebran, Fawad; Kutschka, Ingo; Gerecke, Birgit; Hellenkamp, Kristian; Beuthner, Bo; Evertz, Ruben; Bader, Niklas; Priesmeier, Laura; Riedemann, Gabriel; Danner, Bernhard; Sadlonova, Monika; Bosselmann, Lena; Lotz, Joachim; Zimmermann, Wolfram-Hubertus; Tiburcy, Malte; Baraki, Hassina; Didié, Michael; Wehrhahn, Stefanie; Warneck-Telezki, Juliana; Müller, Carolin; Ritter, Christian; Kowallick, Johannes; Ensminger, Stephan; Eitel, Ingo; Jurczyk, Dominik; Graf, Tobias; Paitazoglou, Christina; Busch-Tilge, Claudia; Fujita, Buntaro; Pühler, Thomas

Forschungszentrum DZNE1d ago
New paper out: Gene deletion of Klotho in the dentate gyrus does not affect the number of adult-born granule cells.: Kraus, Patrick; Marunde, Monika; Ryzynski, Alexandre; et al.
Scientific reports Vol. 16, no. 1, p. 16415 http://dlvr.it/TStw86 | Please share #dzne #papers
Gene deletion of Klotho in the dentate gyrus does not affect the number of adult-born granule cells. - DZNEPUB

Overexpression and exogenous administration of the anti-ageing hormone Klotho has been shown to enhance and promote adult hippocampal neurogenesis. However, whether locally produced Klotho from dentate gyrus neurons contributes to this process has remained unclear. Here we show that conditional gene knockout of Klotho in granule cells of the mouse dentate gyrus results in a temporally restricted reduction of immature neurons (days 7-17 post-mitosis), but does not affect stem cell proliferation or long-term neuronal survival. Thus, the role of local Klotho expression is not essential for functional maturation and integration of adult-born neurons. Kraus, Patrick; Marunde, Monika; Ryzynski, Alexandre; Düzel, Emrah; Kaether, Christoph; Kreutz, Michael R; Oelschlegel, Anja M

Forschungszentrum DZNE1d ago
New paper out: AI software as a third reader in breast cancer screening-a prospective diagnostic observational study.: Lehnen, Thomas; Polenske, Doris; Wichtmann, Barbara Daria; et al.
European radiology Vol. 36, no. 6, p. 4478 - 4488 http://dlvr.it/TStggw | Please share #dzne #papers
AI software as a third reader in breast cancer screening-a prospective diagnostic observational study. - DZNEPUB

Despite advances in mammography screening, some cancers remain undetected, prompting the evaluation of artificial intelligence (AI) as an independent third reader to reduce missed cancers.In this prospective study, women eligible for the German Mammography Screening were enrolled at six sites belonging to one screening unit between August 2023 and February 2024. Each mammogram underwent double reading and was independently analyzed using Transpara, an AI-based detection software. Cases rated BI-RADS 4 or 5 by any reader or given a risk score of 10 by the software were reviewed in a consensus conference. Endpoints included: primary-cancer detection rate (CDR) and positive predictive values (PPV); secondary-analysis of cancers detected only by the software or missed by it.15,356 female participants (mean age 58.6 ± 5.6 years) were included. Overall, 115 breast cancers were detected (CDR triple reading: 0.75%; 95% CI: 0.62%, 0.90%). CDR of double reading and standalone AI was 0.68% (95% CI: 0.56, 0.83%) and 0.66% (95% CI: 0.54, 0.81%). Using Transpara as a third reader increased the detection rate by 9.5% (95% CI: 4.7%, 16.8%) compared to double reading (p = 0.002). The PPV for consensus-conference referrals was 5.1% (95% CI: 4.2%, 6.1%), lower than double reading 7.5%(95% CI: 6.2%, 9.0%; p < 0.001). For recalled cases, the PPV was 13.7%(95% CI: 11.5%, 16.2%) versus 15.2% (95% CI: 12.6%, 18.1%; p < 0.001). All nine invasive cancers detected solely by AI were Luminal-A-like cancers. Among 13 cancers missed by the software, four were triple-negative.Adding Transpara as an independent third reader improved detection rates, mainly by identifying additional Luminal-A-like cancers, and increased the workload to the consensus conference and the number of recalled cases.Question Does the integration of AI software as an independent third reader improve cancer detection rates in mammography screening without increasing false-positive findings and recall rates? Findings AI as an independent third reader increased cancer detection by 9.5%, mainly identifying Luminal-A-like cancers, significantly decreasing the positive predictive values of cases referred to at the consensus conference and increasing the number of recalled cases. Clinical relevance Using AI as an independent third reader enhances mammographic cancer detection by offering radiologists complementary sensitivity, especially for low-risk lesions. However, maintaining human readers is essential, as AI may miss aggressive subtypes like triple-negative breast cancers. Lehnen, Thomas; Polenske, Doris; Wichtmann, Barbara Daria; Lehnen, Nils Christian

Forschungszentrum DZNE2d ago
New paper out: Plasma levels of an N‐terminal tau fragment predict Alzheimer's and neurodegenerative disease biomarkers in autosomal dominant Alzheimer's disease: Schultz, Stephanie A.; Rao, Yiwen; Liu, Lei; et al.
Alzheimer's and dementia Vol. 22, no. 1, p. e71049 http://dlvr.it/TStBrm | Please share #dzne #papers
Plasma levels of an N‐terminal tau fragment predict Alzheimer's and neurodegenerative disease biomarkers in autosomal dominant Alzheimer's disease - DZNEPUB

INTRODUCTIONTau species lacking truncation of the N-terminal region, including plasma N-terminal tau fragment 1 (NT1), have been previously associated with cognitive decline, neurodegeneration, and tau pathology in late-onset sporadic Alzheimer's disease (AD).METHODSHere, we examined cross-sectional and longitudinal plasma NT1 as a possible predictor of cognitive, clinical, and core AD biomarker trajectories in autosomal dominant AD (ADAD).RESULTSNT1 levels in ADAD mutation carriers (MC; n = 132) increased across the disease continuum, compared to non-carriers (NC; n = 75), becoming elevated about a decade prior to estimated symptom onset. Cross-sectional and longitudinal NT1 levels in MC were associated with clinical, cognitive, and biomarker changes. NT1 increases continued in symptomatic phases of disease, a distinct trajectory from that seen with CSF p-tau217 and other phospho-tau species.DISCUSSIONTogether, our results suggest that plasma NT1—alone or combined with other tau measures—may be useful in studying AD-related clinical, cognitive, and biomarker outcomes.Highlights Leveraging a deeply phenotyped cohort of individuals carrying a pathogenic variant for autosomal dominant Alzheimer's disease (ADAD) and their non-carrier family members, our results suggest that plasma N-terminal tau fragment 1 (NT1) levels mirrored changes in clinical, cognitive, and neurodegenerative measures in ADAD, particularly in late asymptomatic and early symptomatic phases of disease. NT1 levels correlated with cerebrospinal fluid (CSF) measures of tau pathology but less so with CSF or imaging measures of β-amyloid pathology. Together with previous supportive findings in preclinical and symptomatic sporadic AD, these results suggest that plasma NT1—alone or combined with other tau measures—may be useful in studying AD-related tau pathology and neurodegeneration across a wide spectrum of disease. Schultz, Stephanie A.; Rao, Yiwen; Liu, Lei; Ostaszewski, Beth; Anderson, Amirah K.; Yau, Wai-Ying Wendy; Shirzadi, Zahra; Gordon, Brian A.; Hassenstab, Jason; Morris, John C.; Perrin, Richard J.; Allegri, Ricardo F.; Barthélemy, Nicolas R.; Fox, Nick; Day, Gregory S.; Jucker, Mathias; Levey, Allan I.; Levin, Johannes; Mori, Hiroshi; Salloway, Stephen; Schofield, Peter; McDade, Eric; Sperling, Reisa A.; Bateman, Randall J.; Selkoe, Dennis J.; Chhatwal, Jasmeer P.

Forschungszentrum DZNE2d ago
New paper out: Sphingolipidoses: expanding the spectrum of α-synucleinopathies.: Erskine, Daniel; Bronowska, Agnieszka K; Outeiro, Tiago F; et al.
Journal of neural transmission Vol. 133, no. 5, p. 809 - 821 http://dlvr.it/TSsyH8 | Please share #dzne #papers
Sphingolipidoses: expanding the spectrum of α-synucleinopathies. - DZNEPUB

Although α-synuclein pathology is typically associated with Lewy body diseases and multiple systems atrophy, increasing evidence indicates that it also occurs in a group of lysosomal storage disorders termed sphingolipidoses caused by the incomplete degradation, and subsequent accumulation, of a class of lipids termed sphingolipids. Notably, a number of genes that cause sphingolipidoses are also risk genes for Lewy body diseases, suggesting aetiological links between these distinct disorders. In the present review, we discuss the sphingolipidoses in which α-synuclein pathology has been reported: Gaucher disease, Krabbe disease, metachromatic leukodystrophy, Tay-Sachs disease and Anderson-Fabry disease, and describe the characteristic clinical and pathological features of these disorders, in addition to the evidence suggesting α-synuclein pathology occurs in these disorders. Finally, we evaluate the pathological mechanisms that underlie these rare disorders, with particular attention to how the enzymatic deficiency, substrate accumulation, or both, could contribute to the genesis of α-synuclein pathology and the implications of this for Lewy body diseases. Erskine, Daniel; Bronowska, Agnieszka K; Outeiro, Tiago F; Attems, Johannes

Forschungszentrum DZNE2d ago
New paper out: The PET tracer [11C]MODAG-005 targets alpha-synuclein aggregates in the brain.: Saw, Ran Sing; Haas, Sabrina; Schmidt, Felix; et al.
Science translational medicine Vol. 18, no. 851, p. eaec0813 http://dlvr.it/TSsjQD | Please share #dzne #papers
The PET tracer [11C]MODAG-005 targets alpha-synuclein aggregates in the brain. - DZNEPUB

Synucleinopathies are neurodegenerative diseases characterized by the presence of brain inclusions containing the pathologically aggregated protein α-synuclein. The development of a positron emission tomography tracer to detect aggregates of misfolded α-synuclein could revolutionize early diagnosis, disease monitoring, and the evaluation of therapeutic efficacy. Here, we present the development, preclinical validation, and first-in-human evaluation of [11C]MODAG-005. In vitro binding experiments demonstrated subnanomolar binding affinity to recombinant α-synuclein fibrils and to α-synuclein inclusions in human brain tissue. Specific binding in multiple system atrophy (MSA) brain tissue was detected using autoradiography and microautoradiography and was validated through immunostaining. In vivo, [11C]MODAG-005 showed good brain penetration, rapid clearance from brain tissue, and low metabolite formation in rodents and nonhuman primates. In addition, a pronounced binding and a good signal-to-noise ratio were achieved in an α-synuclein fibril-injected rat model and in an α-synuclein (A30P) transgenic mouse model in correlation to the pathological load. To validate the potential of [11C]MODAG-005 for therapeutic development, we showed target engagement of the drug candidate anle138b in the brain tissues from α-synuclein (A30P) mice and patients with multiple system atrophy as well as in vivo in α-synuclein fibril-injected rats. Last, first-in-human imaging demonstrated [11C]MODAG-005 binding in brain regions affected by α-synuclein pathology in patients with clinically established MSA cerebellar type, MSA cerebellar and parkinsonian type, and Parkinson's disease. Saw, Ran Sing; Haas, Sabrina; Schmidt, Felix; Ryazanov, Sergey; Leonov, Andrei; Bleher, Daniel; Grotegerd, Ann-Kathrin; Kuebler, Laura; Roeben, Benjamin; Schmidt, Fabian; Reimold, Matthias; Bonanno, Federica; Ruf, Viktoria C; Dahl, Bernadette; Sandiego, Christine M; Henry, Kelly E; Papadopoulos, Ioannis; Schaller, Martin; Kahle, Philipp J; Levin, Johannes; Gasser, Thomas; Brockmann, Kathrin; Reischl, Gerald; la Fougère, Christian; Pichler, Bernd J; Maurer, Andreas; Griesinger, Christian; Giese, Armin; Herfert, Kristina

Forschungszentrum DZNE3d ago
New paper out: Characterization of the electrode-tissue interface during long-term deep brain stimulation in the 6-OHDA rat model of Parkinson's disease.: Philipp Payonk, Jan; Kober, Maria; Budde-Sagert, Kai; et al.
Journal of neural engineering Vol. 23, no. 3, p. 036014 - http://dlvr.it/TSsCVf | Please share #dzne #papers
Characterization of the electrode-tissue interface during long-term deep brain stimulation in the 6-OHDA rat model of Parkinson's disease. - DZNEPUB

Objective.Deep brain stimulation is an established therapy for neurological disorders such as Parkinson's disease, but its underlying mechanisms and tissue effects remain incompletely understood. A particular challenge arises from the foreign body response to implanted electrodes, which leads to scar formation and encapsulation, altering the electrical properties of the surrounding tissue. This study aims to characterize the electrode-tissue interface during long-term stimulation and to improve model-based estimation of the stimulation volume using subject-specific dielectric properties.Approach.Continuous deep brain stimulation was delivered for six weeks using a fully implantable stimulator in a unilateral 6-hydroxydopamine Parkinson rat model.In vivoimpedance spectroscopy andpost mortemhistology were performed to assess encapsulation tissue properties. Principal component analysis was applied to identify group differences in the impedance spectra. Encapsulation layer thickness was quantified histologically and incorporated into subject-specific numerical models to resolve the non-identifiability between layer thickness and dielectric parameters. Dielectric properties were estimated by fitting simulated spectra to experimental measurements.Main results.Impedance spectra differed significantly between stimulated and non-stimulated animals, indicating that impedance spectroscopy can distinguish tissue responses to chronic stimulation. Incorporating subject-specific encapsulation parameters substantially altered estimates of the stimulation volume compared to conventional assumptions.Significance.By integratingin vivomeasurements, histology, and computational modeling, this study replaces generic interface assumptions with subject-specific electrode-tissue properties. The results identify measurable markers of encapsulation tissue and demonstrate that conventional modeling approaches overestimate the stimulation volume when generic interface assumptions are used. Incorporating subject-specific electrode-tissue properties improves the reliability of deep brain stimulation simulations and supports individualized stimulation strategies. Philipp Payonk, Jan; Kober, Maria; Budde-Sagert, Kai; Bernsdorff, Felix; Statz, Meike; Bathel, Henning; Arbeiter, Nils; Fauser, Mareike; Badstübner-Meeske, Kathrin; Bahls, Christian; Krüger, Frank; van Rienen, Ursula; Storch, Alexander; Zimmermann, Julius